1. Field of the Invention
The chemical processes of the present invention provide novel antibacterial agents of the .beta.-lactam type containing a hiterto unknown nucleus and useful intermediates for the synthesis of said antibacterial agents.
2. Description of the Prior Art
Penicillins and cephalosporins comprise a group of well-known antibacterial agents commonly grouped together as a class called .beta.-lactam antibiotics. Most of the work in this field has been done, broadly speaking, with 6-aminopenicillanic acid, 7-aminocephalosporanic acid and derivatives thereof produced by fermentation or chemical transformation of the natural products. Despite the extensive progress made in preparing active derivatives of 6-aminopenicillanic acid and 7-aminocephalosporanic acid, there is a continuing search for synthetic and semi-synthetic routes to new families of .beta.-lactam antibiotics which may possess more advantageous properties than those derived from the known penicillin and cephalosporin nuclei.
Literature publications relating to other more non-conventional .beta.-lactam-containing antibiotics include the following:
A. Belgian Pat. No. 846,933 discloses the compound of the formula ##STR2## which has been isolated from fermentation of Streptomyces clavuligerus. This compound, named clavulinic acid, possesses a low order of antibacterial activity but inhibits the action of certain .beta.-lactamases and reportedly enhances the in vitro and in vivo activity of some penicillins and cephalosporins. PA1 B. U.K. Pat. No. 1,467,413 discloses the fermentation product having the formula ##STR3## which is reported to possess some antibacterial activity and to be a .beta.-lactamase inhibitor. PA1 C. Brown, et al. in J.C.S. Chem. Comm., 359-360 (1977) disclose preparation of the compound of the formula ##STR4## There is no indication from the publication that the compound possesses any antibacterial activity. PA1 d. U.S. Pat. No. 3,950,357 describes a fermentation process for producing thienamycin, the compound of the formula ##STR5## Thienamycin is reported to be a highly potent broad-spectrum antibiotic. e. Belgian Pat. No. 849,118 discloses a series of 6-amino-2-penem-3-carboxylic acid derivatives of the formula ##STR6## where R.sub.1.sup.a is hydrogen or an N-protecting group, R.sub.1.sup.b is hydrogen or acyl (or R.sub.1.sup.a and R.sub.1.sup.b taken together are a divalent N-protecting group), --CO--R.sub.2 is carboxyl or a protected carboxyl group and R.sub.3 is hydrogen or a C-bonded organic group. The compounds and their salts are said to possess antibacterial activity. Example 8 in the Belgian Patent discloses the compound where R.sub.1.sup.a is hydrogen, R.sub.1.sup.b is C.sub.6 H.sub.5 OCH.sub.2 CO--, R.sub.2 is OH and R.sub.3 is CH.sub.3. No compounds are disclosed in the publication which do not contain the amino or acylamido moiety at the 6-position of the .beta.-lactam ring. PA1 (1) thermally cyclizing in an inert organic solvent a phosphorane intermediate of the formula ##STR15## wherein Z represents phenyl or C.sub.1 -C.sub.6 alkyl but preferably phenyl to produce a compound of the formula ##STR16## (2) subjecting the ester of formula I.sub.a to catalytic hydrogenation employing a noble metal catalyst in a non-reducible inert aqueous or non-aqueous solvent in the presence or absence of a base to produce the racemic acid of the formula ##STR17## or a carboxylic acid salt thereof and, if desired, performing one or more of the further steps selected from (a) resolving the so-produced racemic compound into its dextrorotatory and levorotatory optical isomers thereof and recovering the dextrorotatory isomer; and (b) converting the racemic free acid or salt of formula I or the dextrorotatory isomer thereof to a physiologically hydrolyzed ester thereof or a pharmaceutically acceptable carboxylic acid salt thereof. PA1 (a) reacting 4-acetylthio-2-acetidinone of the formula ##STR23## with a glyoxylic acid ester of the formula ##STR24## or a reactive oxo-derivative thereof such as a hydrate in an inert organic solvent, preferably at an elevated temperature, to produce a mixture of epimers having the formula ##STR25## (b) converting the so-produced hydroxy intermediate III to the corresponding chloro epimeric mixture of the formula ##STR26## by treatment with a chlorinating agent in an inert organic solvent in the presence or absence of a base; PA1 (c) reacting the chloro intermediate IV with a phosphine compound of the formula ##STR27## where R.sub.a, R.sub.b and R.sub.c are phenyl or C.sub.1 -C.sub.6 alkyl, preferably phenyl, in an inert organic solvent in the presence of a base to produce the desired phosphorane intermediate II.